Parkinson disease (PD) is an age-associated multi-factorial disorder resulting from a combination of genetic and environmental factors. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of autosomal dominant Parkinsonism. In some populations, the frequency of LRRK2 mutations accounts for as much as 30% of familial PD cases, with G2019S being the most frequent mutation. LRRK2 mutations are also found in some sporadic Parkinsonism patients. Four years have passed since the first mutations in LRRK2 were identified, but the function of Lrrk2 and how mutations lead to PD remains largely unknown. To gain insight into the pathologic mechanisms of the mutations, we have created LRRK2 knock-out and Lrrk2 G2019S knock-in mouse models. These models represent excellent physiological test systems to evaluate the normal and physiological roles of Lrrk2. We will characterize these mice for neuronal vulnerability, neurodegenerative alterations, dopamine release and behavioral alterations, phenotypes that have all been linked to Lrrk2 function. This work should significantly contribute to our understanding of the functional role of Lrrk2 and direct future studies and therapeutic design. PUBLIC HEALTH RELEVANCE: Mutations in the gene LRRK2 cause Parkinson Disease. This proposal aims to use animal models to study the biological manner in which LRRK2 mutations exert their pathogenic effects.